Hyperuricemia is defined by values of blood uric acid over 6.8 to 7.0 mg/dL in men or over 6 mg/dL in women. Hyperuricemia and metabolic disorders associated with hyperuricemia, such as gout, affect 3 to 5 million individuals in the United States. In the United States, African Americans are twice as likely as Caucasian Americans to have gout. Further, gout and hyperuricemia have become common in China, Japan, Polynesia and urban sub-Saharan Africa, with rates of gout approximately doubling between 1990 and 2010. This rise in the incidence of the disease is believed to be due to a longer life expectancy, changes in diet, alcohol consumption and an increase in diseases associated with gout, such as metabolic syndrome, renal insufficiency and hypertension. A number of factors have been found to influence rates of gout, including age, race, and the season of the year. In men over the age of 30 and women over the age of 50, prevalence of gout is approximately two percent.
The metabolic disorders associated with hyperuricemia include not only gout, but also painful attacks of acute, monarticular, inflammatory arthritis due to uric acid crystals, deposition of urate crystals in joints, deposition of urate crystals in renal parenchyma, urolithiasis, nephrolithiasis and gouty nephropathy. Long term nephrolithiasis and gouty nephropathy are known to increase the risk of kidney damage and kidney failure.
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected (in about 50% of cases). However, gout may also present as tophi, kidney stones or urate nephropathy. Gout is believed to be caused by elevated levels of uric acid in the blood which crystallize and are deposited in joints, tendons, and surrounding tissues.
Current treatments for hyperuricemia and gout include lowering the blood concentration of uric acid by urate-lowering agents, such as: 1) xanthine oxidase inhibitors, such as allopurinol and febuxostat; 2) uricosuric agents, such as sulphinpyrazone, benzbromarone and probenecid; 3) urate oxidases, such as pegloticase, puricase, rasburicase and pegylated uricase; and 4) fenofibrate. In addition, the symptoms of acute gout may be controlled by anti-inflammatory agents, such as: 1) non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin and ibuprofen; 2) corticosteroids; and 3) colchicine. Bringing the blood uric acid levels back to the normal range may decrease the incidence of the recurrent acute gout and prevent other metabolic disorders associated with hyperuricemia.
However, many of the currently available treatments for gout or hyperuricemia are associated with a variety of adverse side effects. For example, xanthine oxidase inhibitors, such as allopurinol, are associated with hypersensitivity angiitis, Stevens-Johnson syndrome, exfoliative dermatitis, plastic anemia, and hepatic insufficiency. Uricosuric agents, such as probenecid, bucolome and benzbromarone, have such side effects as gastrointestinal disorders, urinary lithiasis; and fulminant hepatic failure in patients with idiosyncrasies. Further, probenecid may affect the excretion of such drugs as captopril, indomethacin, ketoprofen, ketorolac, naproxen, cephalosporins, quinolones, penicillins, methotrexate, zidovudine, gancyclovir and acyclovir. Long term use of NSAIDs may lead to side effects, including ulcer perforation and upper gastrointestinal bleeding.
Therefore, there is still a need to develop new agents for the treatment of gout and hyperuricemia.